Cocaine addiction is often considered a disease of drive and compulsion. Based on this concept, reward/pleasure per se cannot completely account for compulsive drug intake. The goal of this proposal is to study the neural systems subserving reward and compulsive drug taking in cocaine addiction, and to study the neural circuitry responsible for compulsive drug taking behaviors triggered by both drug-related cues and cocaine itself. Ultimately, our understanding of drug addiction will require the elucidation of how these neuronal circuits interact and contribute to relapse and drug seeking. Therefore, knowledge of the neural mechanisms underlying drug rewarding and cravings should lead to the development of more effective treatment strategies. Our central hypothesis is that both cue-and cocaine-elicited cravings that drive further drug taking commonly activate the orbitofrontal cortex (OFC) and associated cortical and subcortical structures. Once the OFC is activated, the result is an intense drive to get the drug (sometimes perceived as craving), and leads to compulsive drug taking (consciously perceived as loss of control). This hypothesis is supported by many findings from positron emission tomography (PET) and functional MRI (fMRI studies. Nevertheless, the issue of how rewards or cravings result in compulsive drug abuse remains primarily unsolved. There are many factors that contribute to this gap in our knowledge. One roadblock has been the difficulty of simultaneously measuring cue- or cocaine-induced neuronal activity in the region of the OFC and in the region of the nucleus accumbens (NAc). Therefore, tofill this methodology gap, we will develop a customized fMRI-BOLD (blood oxygenation level dependent) acquisition method as proposed in Specific Aim 1. To test our central hypothesis, three sub-hypotheses have been formulated. Specific Aim 2 will test the hypothesis that cue-induced craving associated with comulsive behaviors and relapse is related to activations involving the hippocampus (Hipp)/Amygdala (Amy) to OFC pathways. Specific Aim 3 will test the hypothesis that cocaine-induced craving associated with cocaine binge is related to activations through the dopaminergic mesocorticolimbic (MCL) to OFC pathways. Specific Aim 4 will test that the combination of cue- and cocaine-elicited cravings, similar to the actual context of cocaine experience, will greatly enhance OFC activations and induce intense drive to take the drug.